21-45899581-ATTTT-ATTTTTT

Variant names:

• chr21-45899581-A-ATT
• rs145892465
• NM_001384156.1:c.166-9_166-8dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384156.1(PCBP3):​c.166-9_166-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,345,994 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PCBP3 NM_001384156.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

Genes affected

PCBP3 (HGNC:8651): (poly(rC) binding protein 3) This gene encodes a member of the KH-domain protein subfamily. Proteins of this subfamily, also referred to as alpha-CPs, bind to RNA with a specificity for C-rich pyrimidine regions. Alpha-CPs play important roles in post-transcriptional activities and have different cellular distributions. The protein encoded by this gene lacks the nuclear localization signals found in other subfamily members. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384156.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBP3	NM_001384156.1	MANE Select	c.166-9_166-8dupTT		splice_region intron	N/A	NP_001371085.1	P57721-1
	PCBP3	NM_001348240.2		c.166-9_166-8dupTT		splice_region intron	N/A	NP_001335169.1
	PCBP3	NM_001382279.1		c.166-9_166-8dupTT		splice_region intron	N/A	NP_001369208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBP3	ENST00000681687.1	MANE Select	c.166-18_166-17insTT		intron	N/A	ENSP00000505796.1	P57721-1
	PCBP3	ENST00000400304.1	TSL:1	c.70-18_70-17insTT		intron	N/A	ENSP00000383159.1	E9PFP8
	PCBP3	ENST00000400308.5	TSL:1	c.166-18_166-17insTT		intron	N/A	ENSP00000383163.1	P57721-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000601 AC: 1 AN: 166326 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 14 AN: 1345994 Hom.: 0 Cov.: 28 AF XY: 0.00000448 AC XY: 3 AN XY: 670294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 41154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23954

East Asian (EAS) AF: 0.00 AC: 0 AN: 36592

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.0000127 AC: 13 AN: 1024668

Other (OTH) AF: 0.00 AC: 0 AN: 55602

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145892465; hg19: chr21-47319495;